OVERALL DESCRIPTION (Applicant's Description) We propose experiments in years 26 to 30 of a successful Program to explore the molecular basis on cell transformation. The six participating laboratories will carry out investigations into the role of viral gene products, interacting cellular proteins, and mutagenesis in cell transformation. The six participating laboratories will carry out investigations into the role of viral gene products, interacting cellular proteins, and mutagenesis in cell transformation. Dr. Miller will continue his studies on the mechanism of viral transactivators that disrupt herpesvirus latency. Dr. DiMaio will continue to analyze the effect of papillomavirus E2 proteins, as well as the viral E6 and E7 oncogenes, on the proliferation of human cervical cancer cells, with the goal of determining the molecular basis for the effects observed. Dr. Glazer will study the mutagenic effects of cytomegalovirus oncogenes that employ a "hit-and-run" mechanism of cell transformation. In another project centered on mutagenesis, Dr. Sweasy will explore the consequences of cancer-associated mutations in DNA polymerase beta on protein function and cellular physiology. Dr. Maizels' project focuses on chromosomal telomeres and cellular proteins involved in telomere maintenance. Finally, Dr. Steitz will continue her studies establishing the biochemical activities of virally-encoded small RNAs and determining their effects on host cell function. In addition, a protein expression and purification core will provide essential services to the Program. This Program represents the significant commitment of the Yale University School of Medicine and the participating investigators to studies that may well have direct relevance to understanding the cause of human cancer.